The abundance of genomic data from infectious microorganisms provides a wealth of information that may now be used to identify antigen targets for subunit vaccine development. Here we propose a strategy employing bioinformatics together with high throughput proteomics to rapidly identify target antigens from large and complex genomes, using Plasmodium falciparum as a model. Protective immunity to malaria can be induced by exposure to intact parasite. However, more than 5000 proteins are expressed during the life cycle of the Plasmodium spp. parasite, and the protein antigens mediating the protective immunity induced by whole organism vaccination are largely unknown. Only a small number of potential targets have been identified to date. Subunit vaccines currently in development are based on a single or few antigens and may therefore elicit too narrow a breadth of response, providing neither optimal protection nor protection on genetically diverse backgrounds. A high throughput protein _expression platform technology, called PCR Express, has been developed which can be used to rapidly generate the complete proteome from any sequenced microorganism. PCR Express allows thousands of different genes to be cloned, expressed and printed onto protein microarray chips, at a rate of more than 300 proteins per week. The chips can be used to scan serum from vaccinated or infected animals and humans and the immunodominant antigens identified. This valuable knowledge can then be immediately parlayed into additional areas of proposed research: 1) diagnostic tools for measuring malaria immunity in vaccinees; 2) development of simple, rapid, and sensitive immunological tools for assessing recent malaria exposure/ infection; 3) development of therapeutic anti-malaria neutralizing monoclonal human antibodies; 4) development of safe and effective candidate subunit malaria vaccines; and 5) accurate assessment of the quality of the immune responses elicited by alternative malaria vaccines. Of particular importance, there is a serious need for a malaria vaccine and the data generated from this application will be used to identify likely protective antigen candidates for a DNA or protein subunit vaccine against malaria.